Substituted benzofurans

ABSTRACT

Benzofurans and 2,3-dihydrobenzofurans optionally substituted at the 2 position by halogen or lower alkyl, substituted at the 3 position by optionally substituted phenyl, substituted on the benzo ring by a lower alkanoic acid group or a salt, ester or amide thereof, optionally substituted on the carbon of said lower alkanoic group bonded to the benzo ring, and optionally substituted on the benzo ring, are active anti-inflammatory, anti-pyretic and analgesic agents or are intermediates in the preparation of such agents.

United States Patent. [191 Scherrer 1 Nov. 18, 1975 v [75] Inventor:

[ SUBSTITUTED BENZOFURANS Robert A. Scherrer, White Bear Lake, Minn.

[73] Assignee: Riker Laboratories, Inc.,

Northridge, Calif.

[22] Filed: July 31, 1974 [21] Appl. No.: 493,215

Related US. Application Data [62] Division of Ser. No. 199,318, Nov. 11, 1971, Pat. No.

[52'] US. Cl. 424/285 [51] Int. Cl. A61K 31/34 [58] Field of Search 424/285 [56] References Cited UNITED STATES PATENTS 3,682,976 8/1972 Kaltenbronn 260/3462 R Primary Examiner-Stanley J. Friedman Attorney, Agent, or FirmAlexander, Sell, Steldt & DeLaHunt 57 ABSTRACT "1'7 Claims, No Drawings SUBSTITUTED BENZOFURANS This is a division of application Ser. No. 199,318 filed Nov. 11, 1971 [1.8. Pat. No. 3,862,134.

The present invention relates to benzofurans and 2,3- dihydrobenzofurans optionally substituted at the 2 position by halogen or lower alkyl, substituted at the 3 position by optionally substituted phenyl, substituted on the 5,6 or 7 position of the benzo ring by a loweralkanoic acid group or a salt, ester or amide thereof, optionally substituted on the carbon of said lower alkanoic group bonded to the benzo ring, and optionally substituted on the benzo ring.

The compounds of the invention are anti-inflammatory agents, or intermediates for the synthesis thereof. Certain benzofuran derivatives containing both phenyl and acetic acid substituents are knownf to the art. See various publications by J. N. Chatterjea. However, these compounds contain the alkanoic acid substituent on the heterocyclic furan portion of the compound, not the benzo fragment of the benzofuran moiety. In addition, both the 2 and the 3 positions of thefuran ring of the'compounds of the prior art are interchangeably substituted by the phenyl and acetic acid substituents. The compounds of the art have no known use. In particular they are not known to be active as pharmaceuticals.

It is an object of the invention to provide compounds which are anti-inflammatory agents.

It is an object of the invention to provide compounds which are anti-pyretic agents.

It is an object of the invention to provide compounds which are analgesic agents.

It is a further object of the invention to provide a method for controlling inflammation in mammalian tissue.

It is a further object of the invention to provide a method for controlling fever. I

It is a further object of the invention to provide a method for relieving pain.

It is still another object of the invention to provide anti-inflammatory compositions containing one or more substituted benzofurans and 2,3-dihydrobenzofurans as active ingredients therein.

It is still another object of the invention to provide anti-pyretic compositions containing one or more substituted benzofurans and 2,3-dihydrobenzofurans as active ingredients therein.

It is still another object of the invention to provide analgesic compositions containing one or more substituted benzofurans and 2,3-dihydrobenzofurans as active ingredients therein.

It is still another object of the invention to provide novel intermediates in the preparation of the anti-inflammatory, anti-pyretic and analgesic agents of the invention and processes using the novel intermediates to prepare the active agents.

Still other objects will be made apparent by the following specification.

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, there is provided a class of compounds of the formula I 9 i o n 2%? 3 I wherein:

Z is hydroxyl, lower alkoxy, NH Nl-IY,

NY Y

lyi

Nl-IOH NI-INI-I v R is hydrogen or alkyl containing not more than two carbon atoms;

R is hydrogen or, with R, forms =CH R and R are hydrogen or, together, a carbon-carbon bond; R is hydrogen or lower alkyl, provided that when R and R form .a bond, R may be halogen; Y and Y are lower alkyl or, together, form a cyclic Y is lower alkyl, lower alkoxy, halogen, nitro, diloweralkylamino or hydroxyl; Y is lower alkyl, halogen, lower haloalkyl, lower alkoxy, lower haloalkoxy, nitro, diloweralkylamino, lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl or hydroxyl; m is 2-3; n is 0-2; p is 0-2 and r is 0-5. Preferably the carbon atom carrying R and R is substituted at the 6 or 7 position of the benzofuran structure. The invention also includes pharmaceutically acceptable salts of theacid-form compounds (the compounds in which Z isOI-I). The word lower in the foregoing and elsewhere herein indicated a group containing not more than four carbon atoms.

The acid-formzcompounds of the invention and the pharmaceutically acceptable salts thereof, are useful as intermediates .toprepare the acids. In most cases the esters and amides appear to be converted in vivo to the active acid, and thus they provide pharmaceutical activity of themselves. In addition, the esters and amides have different physical properties, for example solubility. Such a variety of physical properties can be useful to maximize the biological availability of the parent acid by varying'the absorption, blood transport, and the like, of the pharmaceutical compounds. In addition, as is known, longer chain fatty acids are degraded in vivo to the lower acid having two less carbon atoms. Thus a 7-benzofuranbutyric acid is considered the metabolic equivalent of the corresponding 7-benzofuranacetic acid in most mammalian species. The corresponding '3- l' iydroxy-butyric acid is the intermediate and hence also is equivalent metabolically to the acetic acid (which has two fewer carbon atoms).

Preferably, in the compounds of the invention, r is -2. Presently those compounds wherein are most preferred.

Additional preferred classes of compounds of the invention are those wherein the phenyl substituent on the furan ring is unsubstituted or halo substituted (especially by fluorine or chlorine, most preferably fluorine); wherein p is zero; and wherein n is zero or one (most preferably wherein n is zero). Preferably also R is hydrogen.

In compounds of the invention, wherein R is hydrogen and R is not hydrogen, the carbon atom to which R is chemically bonded is an asymmetric carbon atom. In this case the compounds of the invention are generally present in the form of a racemic mixture. The resolution of such racemates can be carried out by a number of known methods. For example, someracemic mixtures can be precipitated as eutectics instead of mixed crystals and can thus be quickly separated and in such cases can sometimes be selectively precipitated. The more common method of chemical resolution is, however, greatly preferred. By this method diastereomers are formed from the racemic mixture by reaction with an optically active resolving agent. Thus, an optically active base can be reacted with the carboxyl group. The difference in solubility between the diastereomers formed permits the selective crystallization of one form and regeneration of the optically-active acid from the mixture. There is, however, a third method of resolving which shows great promise. This method is one of the other forms of biochemical procedures using selective enzymatic reaction. Thus, the racemic acid can be subjected to an asymmetric oxidase or decarboxylase form, leaving the other form unchanged. Even more attractive is the use of a hydrolysase on a derivative of the racemic mixture to form preferentially one form of the acid. Thus, esters or amides of the acids can be subjected to an esterase which will selectively saponify one enantiomorph and leave the other unchanged.

on w@ +arc :i-iAr @Q resolving methods, preferably working from the free 65 acid as the starting material. For example, amide or salt diastereomers of the free acid may be formed with optically-active amines, such as quinine, brucine, cinchonidine, cinchonine, hydroxyhydrindamine, menthyla- 4 mine, morphine, a-phenylethylamine, phenyloxynaphthylmethylamine, quinidine, l-fenchylamine, strychnine, basic amino acids such as lysine, arginine, amino acid esters and the like. Similarly, ester diastereomers of the free acid may be formed with optically-active alcohols, such as borneol, menthol, 2-octanol and the like. Especially preferred is the use of cinchonidine to give the readily decomposable diasteromer salt which may then be resolved by dissolving in a solvent, such as acetone, and distilling the solvent at atmospheric pressure until crystals begin to appear and further crystallization produced by allowing the mixture to cool to room temperature, thereby separating the two enantio- ,morphs. For example, the (d) acid may then be recovered from the (d) salt by extracting the salt between an inorganic solvent, such as petroleum ether, and dilute hydrochloric acid.

Derivatives of the resolved form of the free acid then may be prepared in the usual way. These derivatives generally are more active than derivatives of racemates of the same compounds. Consequently, the biologically active form of these compounds substantially free of the other form, is a still further aspect of this invention. The active form is generally the (d) form but absolute rotation and even the sign of rotation of the more active form can vary with substitution and compounds must be tested in biological assays to establish their relative activity.

Compounds of the invention wherein R and R together form a methylene group (=CH are all useful as intermediates, but some are also biologically active.

The compounds of the invention are prepared by multistep synthetic sequences. The most convenient of these start with substituted phenols and form substituted benzofuran derivatives. The substituted benzofuran derivatives are then reacted to obtain the aliphatic acid side chain on the benzo ring. Those skilled in the art will recognize that many variations of these sequences exist. The following discussion describes some of the useful processes for obtaining substituted benzofuran derivatives. The temperatures are given in degrees Centigrade. The definitions of the various moieties, such as W, 0,, Ar, etc. are uniform unless otherwise noted.

PROCESS A This process can be represented as follows:

OCHCAr 0 Q wherein W is bromine, chlorine, iodine or methyl, Q is hydrogen or lower alkyl and Ar is C H -Y as in formula l.

The reactants in step (1) are generally known to the art. Equimolar amounts of the reactants, or an excess of the phenol, are reacted in the presence of a base, generally'a weak inorganic base such as an alkali metal carbonate. A solvent is used, for example glyme, tetrahydrofuran, ethanol, pyridine and the like and an inert atmosphere may be used. The reaction is carried out at from about 50 to the reflux temperature. The compound of formula II is isolated by conventional methods such as extraction or elution chromatography. Compounds ll wherein W is halogen are known.

ln' step (2) the compounds of formula ll are cyclized by heating in polyphosphoric acid. The known comw ocu c onk I PROCESS B Step (3),.the decarboxylation, is carried out by any of i i ocaiis on 9. a I r 9 w tar-elm: (1) Y 0 9 (2) con:

'O-OOAIK 0 Ar Iv methyl Grignard reagent. ln step (3) the-methyl ketone is converted to a carboxylic acid by, for example, the

Willgerodt reaction.

PROCESS D W V 0 I q O O 0 OAIK I Ar A! I Q I M The reactants of step (I) are known compounds, readily cyclized in base such as sodium ethoxide in ethanol to the corresponding benzofurans (VI). The compounds of formula VI are isolated by extraction.

In step (2) the hydrolysis of the ester to the acid is carried out under acidic or basic conditions. Alternatively, if W is methylQhydrolysis is preferably preceded by bromination of the methyl group with N-bromosuc cinimide under free-radical conditions such as are known to the art, followed -by reaction with an alkali metal cyanide to givecyanomethyl derivative.

Alk herein is lower'alkyl. Steps l and (2) are'essen- 40 the well-known methods employed in theart, for examtially the same as steps (I) and (2) of Process A. The

ple heating in quinoline in the presence of a copper catreaction of step (1) uses generally known reactants. alyst. The compounds of formula IV are known. PROCESS E CH-CO AIk QH-COAIK Alto 1006 Y ,5 .61. 6... S (1 0 Ar on 0611 00 513 Y herein is hydrogen, lower alkyl, lower alkoxy,

PROCESS C I Hal herein is chlorine, bromine or iodinefWhen this halogen or dialkylamino. The group method is used, R and Y may not be halogen, and Ar is not substituted by halogen. In step (I) the benzofuran is reacted with cuprous cyanide in a solvent such as quinoline. Step (2) is the reaction of the nitrile with cannot be ortho to the hydroxy group in the reactants of this process. In step (1) a phenoxyacetie ester is 3,920,828 7 8 formed as previously described in Process A, step (1'). The synthetic sequences whereby benzofuran inter- In step (2) the cyclization is carried out as described mediates are converted to compounds of formula I, in Process A, step (2) to give the novel intermediate particularly carboxylic acids, are described further Vlll. When Y is hydrogen, cyclization may occur at ,hereinbelow. either of the positions ortho to the group OCII'- 5 CO Alk on the benzo ring, and when these positions PROCESS F h Bu-1 CH 0 2 v @i m.) 1 Ar Ar v A:- l

CH COOH o aq o CB IDI o @Q} @Q) @Lg Ar b Ar Ar are non-equivalent, two different isomeric products are s (1) may b i d t b any of the well-known formed. These isomers are separated by conventional thod fo pre aring Grignard reagents; tetrahydromethods such as elution chrom graphy, vapor Phase furan is a preferred solvent. Step (2) may be carried chromatography, fractional crystallization, and the out b a d d G -i d ti i h f ld like. hyde, with subsequent acidification to the alcohol. Step The interm diates f f r la "1, V, and 811 (3) requires displacement of the hydroxyl by a halide contain the benzofuran nucleus with an aryl substituent by any of the well-known methods of the art; for examat the 3 position. These intermediates are then used in ple reaction with a hydrohalogen acid, a phosphorus further synthetic sequences wherein the objective is to acid or thionyl halide, or conversion to the mesylate or provide compounds which also include the radical tosylate. The reaction is preferably carried out in an inert solvent (for example benzene, toluene, xylene and the like) with thionyl chloride at any suitable temperaz ture, but especially in benzene at reflux temperature 2 until the reaction is substantially complete.

v .The displacement of the halide with a cyanide by any on the behze ""8 as defined heremaboveof the well-known methods of the art is the reaction of The compounds of formula are hf 1 step (4). Suitable inorganic cyanides, for example soformhla l which may be hydrolyzed under or dium cyanide, potassium cyanide and the like, are rebasic conditions to Provide other compounds of 40 acted in an inert solvent, such as dimethylsulfoxide, mula l wherein the radical the behze ring is v dimethoxyfuran, acetone, aqueous alcohol and the like.

As an example the reaction is carried out in an acetoneeth'anol-water mixture with potassium cyanide at any suitable temperature, for example at the reflux temperature of the reaction mixture until the reaction is sub- Furthermore, compounds of formula VIII may be transtamiauy completa seetenfied usfng f' known to the art such as In step (5) the reaction is hydrolysis of the nitrile by and: or bas'c catalysls' The m 'l 9 formula any of the variety of the methods well-known to the art, VIII may be converted to carboxyllc acid halides by rethe! is acidic, or basic hydrolysis, preferabiy basic action with the usual reagents such as thionyl chloride 50 drolysis with an alkali metal hydroxide in ethanol and phosphorus pentachloride. The acyl halides can 7 then be converted to amides, esters, salts or acids. a PROCESS G 9!! 9|! & CH -C'C0 A1k CH -C'COOH O l o A! v Ar r cu coou cl-i ecwoon (3) Ar Ar 9 10 In step (1) the Grignard reagent is reacted with an ods well known to the art. alpha keto ester, preferably ethyl pyruvate under any of Step (4), simultaneous hydrolysis of the ester and the the well-known Grignard condensation type reaction nitrile is carried out by vigorous hydrolysis with an alconditions. In step (2) hydrolysis is accomplished by kali metal hydroxide in ethanol.

any means well-known to the art. Step (3) is carried out 5 Step (5 selective decarboxylation, is carried out by by any dehydration procedure well-known to the art. heating in a quinoline-pyridine mixture until about one Step (4) is catalytic reduction by methods wellmole of carbon dioxide evolved. known to the art such as reduction over a catalyst, for Step (6), decarboxylation, is carried out as described example palladium, palladium on carbon, platinum, 10 in step (3) Process (D). Raney nickel, platinum oxide and the; like preferably Step (7), hydrolysis of the nitrile, is carried out by the under moderate hydrogen pressure (5 to 60 pounds) in methods described for step (5 Process (F). an inert solvent such as lower alkanols, aromatic compounds, tetrahydrofuran, acetic acid, dioxane and the PROCESSS l a I 01100 It CEO 1k CH Cg A1lt 2* 0 (2) o 1, A! 7 Ar like at any suitable temperature, 0C. to reflux temperwherein R is methyl or ethyl. ature of the system, preferably at room temperature In step (l) the benzofuranacetic ester is converted to until the reaction is substantially complete. the reactive anionic intermediate by the action of a strong base such as sodamide, sodium hydride, lithium PROCESS H N,N-dialkylamide and the like. The anionic intermedi- CH CH HII I; c on o c o iux o i a H2 0 "w Ar Ar Ar 3/ I 03 cm 0 CH2 0 coon \("l O c'u co a coon Ar Ar 0 03 0005 4/ I Ar In step (1) the benzofuran is reacted with a haloate is used without isolation for step (2). genating agent. Presently preferred is N-bromosuccinimide. Free radical conditions which promote side chain In step (2) alkylation is carried out by reaction with halogenation are required, for example cobalt stearate an alkyl halide such as methyl bromide, methyl iodide and tertiary-butyl hydroperoxide y be used as a and ethyl bromide in an inert solvent such as benzene, lyst combination, and a strong source of visible light is diethyl ether, im lfo id and the i at any commonly f suitable temperature from -80 to reflux temperature p i p m n of the halide with a y i is until the reaction :is substantially complete. carried out as described in step (4), Process (F).

Step (3), hydrolysis of the ester, is carried by meth- PROCESS J R cu cn cu ecucu cir ni 0 0 o o ,2 (3) a Ar Ar 1 1 12 In step (1) the anionic intermediate is prepared as In step l) the dialkyl malonate is treated with strong described in step (1), Process (I). In step (2), the alkybase such as sodium hydride, then reacted with the lation is carried out as described in step (2), Process halomethyl-3-arylbenzofuran, preferably in ethanol. In (I). The hydrolysis of step (3) is carried out as destepv (2) decarboxylation is readily effected by known scribed in step (5), Process (F). 5 methods, for example by heating the dry solid reactant t 150 t 200. PROCESS K p I R cnco nk v 1 O 2 O @1) Ar r Step l) is a Grignard reaction of a tert butyl alpha- Compounds of the invention wherein Y is not hydrohaloacetate, alpha-halopropionate or alpha-halobutygen are prepared by the processes A through N derate by methods well known to the art. Step (2) is the scribed hereinabove by incorporating the substituents hydrolysis of the ester under known acidic or basic 0011- in the starting phenols, or by appropriate reaction of ditions. the intermediates as would be apparent to one skilled in PROCESS L the art. Other transformations of one substituent to an- 1 ii 0 R5 x} 5 ac(cu (1) ac(c n Ar Ar ln this process, R must be hydrogen or alkyl. The reother on the structure of formula I, constitute addiduction is carried out as in Process G, step (4) but retional processes for the preparations of these comquiring a longer time or more vigorous. condition. An pounds. Thus Y,, is transformed to another Y and/or example is the use of a catalyst in a lower alkanol such Ar is converted to another Ar and/or R to another R as ethanol as the solvent. The comparable dehydrogenby methods familiar to those skilled in the art. ExamatiOn reaction can also be utilized to f rm C mP und ples include reactions as halogenation, nitration, reducof the invention utilizing known techniques, e.g. heati Qfa nitrogroup to an amine, alkylation of hydroxy ing in decalin in the presence of palladium 0n Char al. groups and amines and oxidation of sulfides to sulfoxides.

CH3 o o o o I 11.1 Halli 1 A1 Ar PROCESS M Ar Ar CH COOH 0 t w m1 Ar In step l the 2 position is halogenated with rnolecu- The processes descrrbed are illustrative of procelar halogen, preferably in an inert solvent. Chlorine and dur'es useful for obtaining the compounds of this invenbromine are the preferred halogens. Step (2) is sidetion but are not intended to be limiting. Other prochain halogenation effected as described in step l cesses are known and may be applied by those skilled in Process H. Step (3) is carried out as described in step the art to obtain the compounds of this invention. (4), Process F. Step (4) is effected using the methods In order to determine and assess the pharmacological of step (5), Process F, preferably using acidic condi? activity of the compounds of the invention, testing in tions. animals is carried out using various assays known to PROCESS N those skilled in the art, for example, the carrageenan or (2001! H51 CH 9 (1) CH CEOOH (2) O 0/ OH (COA1k) w cu cit cooa 1 o Ar Ar bradykinin induced rat foot edema test, the inhibition of ultraviolet-light-induced erythema test (guinea pig), the rat adjuvant arthritis assay, the Randall-Selitto assay, the phenylquinone writhing assay for analgetic activity and the like. Leading references'to the rat foot edema test are:

l. Adamkiewicz et a1., Canad. J. Biochem. Physic.

33:332, 1955; 2. Selye, Brit. Med. J. 2:1129, 1949; and 3. Winter, Proc. Soc. Exper. Biol. Med. 111:554,

1962. Leading reference to the guinea pigerythema test are:

l. Wilhelmi, Schweiz. Med. Wschr. 79:577; 1949,

and I 2. Winder et al., Arch. lnt. Pharmacodyn. 1161261,

The compounds of this invention have a high degree of anti-inflammatory activity and are of value in the treatment of arthritic disorders and like conditions which are known to respond to treatment by drugs with anti-inflammatory activity. In addition, the compounds of the invention have a useful degree of antipyretic and analgesic activity. For these purposes they are normally administered orally in tablets or capsules, the optimum dosage depending upon the particular compound being used and the type and severity of the condition being treated. Although the compounds of the invention are preferably administered orally, they may also be administered parenterally or by suppository.

Compounds of the invention are active in one or more of the standard assays. Preferred compounds are active at dosages of 100mg./kg. or less in one of the assays listed hereinabove, and most preferred compounds have activity equal to or greater than 'phenylbutazone in one or more of these assays.

The following examples are given for the purpose of further illustrating the procedures of the present invention, but are not intended, in any way, to be limiting on the scope thereof. Thus, while the majority of the examples relate to the acid form compounds (in which Z is 01-1), the other compounds of the invention can also be prepared. Also, although the examples relate for the most part to compounds in which the furan ring is unsaturated, it is understood that those compounds in which the furan ring is saturated (R and R are hydrogen) are also contemplated. The melting'points are uncorrected, the temperatures are in degrees Centigrade and the pressure in millimeters of mercury. I

EXAMPLE 1 Process A,step (1) Phenacyl bromide (475 g., 2.38 mole) is added to a mixture of 2-bromophenol (400 g., 2.3 mole) and p tassium carbonate (470 g., 3.46 mole) in glyme (1600 ml.) under a nitrogen atmosphere and the stirred mixture is heated to reflux temperature and maintained at reflux for eight hours. Some solid is presentJThe liquid portion is decanted,'then evaporated to dryness. The residue after this evaporation is boiled in benzene and filtered.

The solid pot residue remaining after decanting is extracted with hot benzene several times, and these benzene extracts are combined with the benzene filtrate. Hexane is added to the cooling benzene and a first crop collected. Partial evaporation gives a second crop. The white solid is alpha-(2-bromophenoxy)acetophenone,

m.p. 1l3.5l 15 C. a

EXAMPLE 2 Process A, step (2) Polyphosphoric acid (4200 g.) and alpha-(2-bromophenoxy)acetophenone from Example 1 (596 g., 2.05 mole) are heated and stirred well at about 120 to 125 C. internal temperature for four hours. The reaction mixture is, then poured into stirred ice and water (about 8 1. total volume) to give a suspension of white solid. The solid is collected and washed with water, cold dilute sodium hydroxide solution and water until the wash is neutral. The solid is recrystallized from hexane to give white crystals of 7-bromo-3-phenylbenzofuran, m.p. 7274 C.

7-methyl-3-phenylbenzofuran is obtained by cyclizing the required acetophenone at about C. for one to 2 hours. The optimum temperature and times vary with other substituents which may be present.

Additional novel intermediates of this type prepared by the general method of Process A illustrated by Examples 1 and 2 include:

6572 C. 7-chloro-3-phenylbenzofuran, m.p. 75.576.5 C.

7-bromo-3-'(2-chlorophenyl)benzofuran, m.p.

7-bromo-5-methyl-3-phenylbenzofuran,

EXAMPLE 3 Process G, steps (2) and (2) Dried magnesium turnings (46.2 g., 1.92 mole), dry tetrahydrofuran (200 ml.) methyl iodide (1 ml.) and a small portion of 7-bromo-3-phenylbenzofuran from Example 2 (total 465.7 g., 1.71 mole) are placed in a dry reactor. After the Grignard reaction is observed to be initiated the remaining benzofuran (diluted with 1 liter of tetrahydrofuran) is added gradually over 1.5 hours at a rate sufficient to maintain moderate reflux. Heating is continued an additional fifteen minutes, then the mixture is allowed to cool.

Ethyl pyruvate (400 g., 3.45 mole) in dry tetrahydrofuran (3 1.) is cooled to -50 C. and the Grignard mixture is added slowly while maintaining the reaction temperature below 35 C. The mixture is stirred well while allowing it to warm to room temperature over 7 hours. The mixture is then heated to its reflux temperature and maintained at reflux for 1 hour. The mixture is evaporated in vacuo to concentrate it to about 1.5 liters. To this concentrate is added concentrated hydrochloric acid (200 ml.) and 1.5 liters of a mixture of ice water. The organic phase is separated and the aqueous phase is extracted twice with dichloromethane. The organic phase is combined with these extracts and the solution is washed with saturated sodium chloride solution, then dried and concentrated by evaporation in vacuo to about one liter of an oil which is chiefly ethyl 2-hyd roxy-2-[ 7-( S-phenylbenzofuran -propionate.

This oil is dissolved in three liters of ethanol and 200 ml. of water and the mixture is heated toits reflux temperature. A solution of potassium hydroxide (232 g.) in water (400 ml.) is added over about one hour. The mixture is maintained at its reflux temperature for 3.5 hours. The mixture is then concentrated to about one-half of its volume and the residue is poured into cold water (1.5 1.). The cloudy mixture is extracted with diethyl ether (700 ml. portions).

The aqueous phase is poured into excess dilute hydrochloric acid and the mixture is cooled and acidified with hydrochloric acid. The solid is collected by filtration and washed with several portions of hot water, then with petroleum ether. The white solid is 2- hydroxy-2-[7-(3-phenylbenzofuran)lpropionic acid, m.p. 112.5-117 C.

Another novel compound of the invention prepared by the general method illustrated by Example 3 is 2- hydroxy-2-{7-[3-(2-methylpheny1)benzofuran]}propionic acid, m.p. 166-166.5 C. In general the hydroxy acid may be used directly as obtained for the next step.

EXAMPLE 4 Process G, step (3) Dry 2-hydroxy-2-[7-(3-phenylbenzofuran)]propionic acid (337 g., 1.19 mole) in toluene (3 1.) under a nitrogen atmosphere is treated with para-toluenesulfonic acid hydrate (70 g.) and hydroquinone (l g.) while refluxing to azeotropically remove water in a Dean-Stark trap. After refluxing for three hours the reaction mixture is cooled, diluted with hexane and cooled by an ice bath. The solid product is collected by filtration washed with petroleum ether, then aqueous ethanol to give 2-[7-(3-phenylbenzofuran)]acrylic acid, m.p. 195.5198.5 C.

Additional novel compounds of the invention prepared by the general method illustrated in Example 4 include:

2-[7-(2-methy1-3-phenylbenzofuran)lacrylic acid,

m.p. 18018l C. 2-{7-[3-(4-chlorophenyl)benzofuran]acrylic} acid,

m.p. 175l81 C. 2-{7-[3-(2-chlorophenyl)benzofuran]acrylic} acid,

m.p. 189-190 C. 2-{7-[3-(3-chlorophenyl)benzofuran]acrylic} acid,

an oil 2-{7-[3-(4-fluorophenyl)benzofuran1acry1ic} acid,

m.p. 204-206 C.

EXAMPLE 5 Process G, step (4) '7rC 72H Calculated for C I-1, 76.7 5.3 5.3

Found: 77.1

Additional novel compounds of the invention prepared by the general method illustrated by Example include:

2-[ 7-( 2-methyl-3-phenylbenzofuran)]propionic acid,

m.p. 146147 C.

16 2-{7-[3-(4-chlorophenyl)benzofuran]propionic} acid,

m.p. 140141 C. 2-{7-[3-(3-ch1orophenyl)benzofuran1propionic} acid,

m.p. 15015l C. 2-{7-[3-(4-fluorophenyl)benzofuran1propionic} acid,

m.p. 169.5171.5 C. 2{7-[3-( 2-chloropheny1)benzofuran1propionic} acid,

m.p. 1s9-190.5 c.

EXAMPLE 6 Process F, steps (1) and (2) Dried magnesium turnings (12.2 g., 0.5 mole), dry tetrahydrofuran ml. methyl iodide (0.5 ml.) and a small sample of 7-bromo3-(4-fluoropheny1)benzofuran (total 134 g., 0.46 mole) are placed in a dry reactor. After the Grignard reaction is observed to be initiated an additional 500 ml. of tetrahydrofuran is added, then the remaining benzofuran dissolved in tetrahydrofuran (500 ml.) is added over one hour at a rate sufficient to maintain a gentle reflux. The mixture is heated for an additional hour, then heating is stopped.

Paraformaldehyde (41.4 g., 1.38 mole) (dried over phosphorus pentoxide), is depolymerized at about 160 C. while passing the formaldehyde vapor into and over the stirred Grignard reaction mixture. The reaction is exothermic, causing a gentle reflux. When reaction is complete, the mixture is concentrated to about onethird of its volume, then poured onto ice and water. Diethyl ether (50 ml.) is added, followed by slow addition of concentrated, cold 6N hydrochloric acid (250-ml.). The mixture is extracted with diethyl ether, the extracts are washed with water and saturated sodium chloride solution, dried and evaporated in vacuo to give an oil. The oil is dissolved in absolute ethanol ml.) and concentrated hydrochloric acid (6 ml.) is added. The mixture is heated to reflux temperature and maintained at reflux for 2.5 hours. The mixture is evaporated in vacuo, then the residue is dissolved in diethyl ether, the solution is washed with water and saturated sodium chloride solution, dried and then concentrated to tan oil crude, 3-(4-fluorophenyl)-7-(hydroxymethyl)benzofuran. Pure product has m.p. 88-89 C.

An additional novel intermediate compound of the invention prepared by the general method illustrated by Example 6 is:

7-hydroxymethyl-3-phenylbenzofuran, m.p. 76-77 C. which can be obtained from either 7-bromo-3- phenylbenzofuran or 7-chloro-3-phenylbenzofuran. The' crude intermediates can advantageously be used directly in the subsequent steps.

EXAMPLE 7 Process F, step (3) 3-(4-Fluorophenyl)-7-(hydroxymethyDbenzofuran (1 10 g., 0.45 mole) is dissolved in benzene (225 ml.) and added dropwise to refluxing thionyl chloride (1 10 ml.). Heating is continued until gas evolution is complete. Excess thionyl chloride and benzene are removed in vacuo, using additional benzene to aid in removing the thionyl chloride. The residue is a brown oil, 7-chloromethyl-3-(4-fluorophenyl)-benzofuran.

EXAMPLE 8 Process F, step (4) To a solution of 7-chloromethyl-3-(4-fluorophenyl)- benzofuran (130.3 g., 0.50 mole) in acetone (750 ml.) and ethanol (500 ml.) is added a solution of sodium cyanide (39.5 g., 0.50 mole) in water ml.). The mixture is heated to its reflux for five hours. The mixture is then evaporated in vacuo to concentrate it. The residue is dissolved in dichloromethane, then washed thoroughly with water, dried and concentrated by evaporation in vacuo. The oily residue is recrystallized twice from cyclohexane, then deposited on 70 g. of a magnesium silicate material used for elution chromatography and chromatographed on 400 g. of the silicate type column. Elution with hexane, benzene-hexane (1:4), (1:1 and (3:2), followed by benzene gives the desired product, 7-cyanomethyl-3-(4-fluorophenyl)benzofuran, in the benzene fractions.

Additional novel intermediate compounds of the invention prepared according to the general method illustrated by Example 8 include:

7-cyanomethyl-3phenylbenzofuran, m.p. 1 ll 1 1 7cyanomethyl-3(4-chlorophenyl)benzofuran, m.p.

EXAMPLE 9 Process F, step Potassium hydroxide (85%, 49 g.), 7-cyanomethyl-3- (4-fluorophenyl)benzofuran (48.8 g., 0.194 mole) and 95% ethanol (500 ml.) are mixed and heated at reflux temperature overnight under a nitrogen atmosphere. The mixture is then concentrated by evaporation in vacuo, diluted with water and extracted with diethyl ether. The aqueous phase is filtered, then acidified by the slow addition of hydrochloric acid. The solid is collected by filtration and recrystallized from aqueous ethanol (65%) with treatment with decolorizing charcoal, giving yellow crystals. Another recrystallization from an ethanol-petroleum ether mixture (about 5:1) gives yellow crystals of 3-(4-fluorophenyl)-7-benzofuranacetic acid, m.p. 169170 C. Analysis:

%C 7:11 Calculated for C,,,H FQ;,: 71.1 4.1 Found: 71.0 3.8

Additional novel compounds of the invention prepared by the general method illustrated by Example 9 include:

3-phenyl-7-benzofuranacetic acid, m.p. 143-144 C.

3phenyl-Sbenzofuranacetic acid, m.p. 131.5132

C. 3-phenyl-7-(5-methoxybenzofuran)acetic acid, m.p.

161162 C. 3phenyl--benzofuranacetic acid, m.p. 143-144 C. 3-phenyl-7-(5-methylbenzofuran)acetic acid, m.p.

l34135 C. (2-methyl-3phenylbenzofuran)-6-acetic acid, m.p.

197198 C. 3-(4-methoxyphenyl)-6-benzofuranacetic acid, m.p.

3-(4-methylphenyl)-6-benzofuranacetic acid, m.p.

3-(4-fluorophenyl)-6-benzofuranacetic acid, m.p.

3-(4-chlorophenyl)-7-benzofuranacetic acid, m.p.

The 5 and 6-acetic acids were prepared by way of the esters, Process E.

EXAMPLE 10 Process L 3Phenyl-7-benzofuranacetic acid (2.5 g., 0.01 mole) is reduced with hydrogen gas using palladium on charcoal as catalyst and ethanol as solvent in a Brown hy- 18 drogenator. After the absorption of hydrogen stops, the reaction mixture is filtered, then the filtrate is evaporated in vacuo to a white solid. Recrystallization from a benzene-hexane mixture gives white crystals of 2,3- dihydro-3phenyl-7benzofuranacetic acid, m.p. 110.5-l 1 15 C.

71C 7: Calculated for C H O 75.6 5.55

' Found: 75.7 5.6

EXAMPLE 1] 2-[7-(3-Phenylbenzofuran)]propionic acid (2.85 g., 0.107 mole) is dissolved in hot chloroform and added to a solution of cinchonine (1.74 g., 0.0059 mole) in chloroform. The clear solution is then concentrated on a steam bath under a stream of nitrogen. Acetone and a little diethyl ether (total about 40 ml.) are added. The solution is cooled and the precipitate is collected (1.7g., m.p. 14l-l46.5 C.). This precipitate is dissolved in a minimum amount (about 45 ml.) of boiling acetone. The total volume is reduced to 35 ml. and the solution is allowed to stand overnight, then cooled. The solid is collected, 1.44 g., m.p. 148.5149 C. Another recrystallization from acetone gives 1.24 g. of white crystals, m.p. 1 4915l C., specific rotation 46 in chloroform. Another recrystallization from acetone gives 1.03 g., m.p. 151.5l52.5 C., specific rotation -4l.5. The free acid is now obtained by stirring with dilute hydrochloric acid in diethyl ether, 0.50 g., m.p. 158.51 61f C., specific rotation +5 8. After recrystallization from a benzene-n-hexane mixture (6 ml:2 m1),

(+)-2-[7-(3-phenylbenzofuran)] propionic acid, 0.40

g., m.p. 1571'62 C., a +58 (chloroform) is obtained. Analysis:

%C %H Calculated for CHHHOQ: 76.7 5.3 Found: 76.7 5.3

, EXAMPLE 12 Process N Diethyl malonate (12.7 g., 0.079 mole) is dissolved in ethanol (40ml.) and treated with sodium hydride (0.079 mole). 7-Chloromethyl-3phenylbenzofuran (10.0 g., 0.0396 mole) is added and the mixture is heated to its reflux temperature and maintained at reflux for ten hours. Equal volumes of water and diethyl ether are added and the ether extracts are evaporated in vacuo. The residue is dissolved in ethanol and potassium hydroxide (16 g.) is added and the mixture is heated on a steam bath. A yellow solid forms rapidly, but heating is continued overnight. The solution is concentrated by evaporation in vacuo, then equal volumes of water and diethyl ether are added. The ether layer is washed with water, dried, then evaporated to dryness. The residue is recrystallized from benzene to give 3- phenyl-7-benzofuranmethylmalonic acid, m.p. 179180 C.

3Phenyl-7-benzofuranylmethylmalonic acid (1.8 g.) is heated to 180 C. dry, with an oil bath. Gas is evolved for about ten minutes. The residue is recrystallized from a mixture of benzene-methanol to give 3-[7-(3- phenylbenzofuran)]-propionic acid, m.p. l61.5-l62.5 C. Analysis:

%C %H Calculated for C H O 76.7 5.3 Found: 76.7 5.3

EXAMPLE 13 2-{7-[3-(2-chlorophenyl)benzofuran1propionic} acid is dissolved in methanol and treated with an equimolar amount of sodium hydroxide. After stirring at ambient temperature for two hours the reaction mixture is evaporated in vacuo to dryness to give sodium 2-{7-[3-(2- chlorophenyl)benzofuran] }propionate, m.p. 22923 1 C. Analysis:

7rC 71H Calculated for C H CINaO 60.0 3.7

Found:

EXAMPLE 14 Proces M, step (1) and (2) 7-Methyl-3-phenylbenzofuran is treated with an equimolar amount of bromine in carbon tetrachloride at room temperature until decolorized. The mixture is concentrated to dryness to remove hydrobromic acid and redissolved in carbon tetrachloride. To this solution is added an equimolar amount of N-bromosuccinimide and catalytic amounts (about one gram/mole of benzofuran) of cobalt stearate and tertiary-butyl hydroperoxide. The mixture is heated to reflux temperature and maintained at reflux for 2 hours while shining a bright floodlight directly upon the reaction mixture. The mixture is cooled, filtered to remove succinimide and concentrated in vacuo to a thick oil which slowly crystallizes on cooling to give 2-bromo-7-bromomethyl-3-phenylbenzofuran, m.p. 135-138 C.

EXAMPLE Process M, steps (3) and (4) A solution of 2-bromo-7-bromomethyl-3-phenylbenzofuran (35.6 g., 0.092 mole) dissolved in a minimum amount of dimethyl sulfoxide is added to a solution of sodium cyanide (5.9 g., 0.12 mole) in dimethyl sulfoxide (50 ml.) and the mixture is heated at 50 to 60 C. for 2 hours. The dark solution is then poured over ice and the solid precipitate is collected by filtration. The product is 2-bromo-7-cyanomethyl-3-phenylbenzofuran.

To a mixture of 50% sodium hydroxide solution (35 ml.) and ethanol (100 ml. is added 2-bromo-7- cyanomethyl-3-phenylbenzofuran phenylbenzofuran (10 g., 0.032 mole). The mixture is heated to reflux temperature and maintained at reflux for about sixteen hours, then concentrated in vacuo. The residue is diluted with water, then extracted (washed) with diethyl ether. The aqueous layer is acidified with hydrochloric acid, yielding a precipitate which is collected by filtration and recrystallized twice from benzene-hexane mix- A %C %H Calculated for C H BrO 58.0 3.3 Found: 58.5 3.2

EXAMPLE 16 Process E, step (3') Ethyl-3-phenyl-5-benzofuranacetate is prepared by cyclization of a-( 4-carbethoxymethylphenoxy)acetophenone in 5 times its weight of polyphosphoric acid at for 30 minutes. Distillation of the crude product gives the desired ester, b.p. ca. l90/0.01 mm, m.p. 43-45 C.

Heating 27 g. of ester overnight in 250 ml. of ethanol with 50 ml. of 50% sodium hydroxide gives 3-phenyl-5- benzofuranacetic acid. m.p. 131.5l32 C. (after recrystallization from aqueous ethanol).

The required aryloxyacetophenone used as starting material is prepared according to the procedure of Example 1.

By the above sequence and starting with methyl phydroxyphenyl propionate there is obtained 3-phenyl- S-benzofuranpropionic acid, m.p. 99.510 C.

EXAMPLE 17 A solution of 40 g., of 3-phenyl-7-benzofuranacetic acid in 400 ml. of ethanol and 40 ml. of sulfuric acid is heated under reflux for 4 hours. The solution is partially concentrated under reduced pressure, poured onto ice and extracted with ether. The ether is washed, dried and concentrated and the residue distilled to give ethyl 3-phenyl-7-benzofuranacetate, b.p. 187189/0.12 mm. Analysis:

%C "/ZH Calculated for CIRHWOH: 77.1 5.7 Found: 77.0 5.8

In a similar manner ethyl 2-[7-(3-pheny)benzofuranyllpropionate is obtained from the corresponding acid.

Methyl 3-phenyl-7-benzofuranacetate is obtained as above using methanol in place of ethanol or by heating the potassium salt of 3-phenyl-7-benzofuranacetic acid with excess methyl iodide in dimethylformaide at 50-60 C. for 30 minutes. -benzofuranacethydraxide, EXAMPLE 18 159 A solution of ethyl 3-phenyl-7-benzofuranacetate, 2.0 g., and hydrazine, l g., in 15 ml. of ethanol is heated overnight at reflux. The mixture is cooled and the white precipitate collected. Recrystallization from benzene gives 3-phenyl-7-benzofuranacethydrazide, m.p. l58l59 C. Analysis:

%C %H %N Calculated for C H N O 72.2 5.3 10.5 Found: 72.3 5.2 10.7

EXAMPLE 19 A mixture of 5.0 g. of ethyl 3-phenyl-7-benzofuranacetate, 2.6 g. of hydroxylamine hydrochloride and 6.3 g. of sodium methoxide in 55 ml. of methanol is heated overnight at reflux. Water and dilute hydrochloric acid are added. The precipitate which forms is collected and recrystallized from ethanol to give 3-phenyl- 7-benzofuranacethydroxamic acid, m.p. 163 (dec). Analysis:

. 71C 71H 7cN Calculated for C H NO 71.9 4.9 52 Found: 71.6 5.1 5.2

EXAMPLE 20 3-Phenyl-7-benzofuranacetamide is obtained by reaction of the acid chloride (from the acid and thionyl chloride in benzene) with ammonia in ethanol. It has m.p. 163-l64.5 C. when recrystallized from ethanolwater.

EXAMPLE 2] Z-Dimethylaminoethyl 2-[7-(3-phenylbenzofuran)]- propionate is obtained by heating 5.0 g. of the propionic acid with 2.7 g. of 2-chloroethyldimethylamine hydrochloride and 3.9 g. of triethylamine in 25 ml. of dimethylformamide for 24 hours. The product is isolated by dilution with 50 ml. of ether, filtration to remove triethylamine hydrochloride, 'and extraction into hydrochloric acid, from which it is freed with sodium carbonate. The ester is an oil, It can be purified as the hydrochloride, m.ps 186l 87 after recrystallization from isopropanol. Analysis:

V v %c %H %N Calculated for C H No Hclz 67.5 6.5 3.7 Found: 67.6 6.6 3.8

'- EXAMPLE 22 3-Pheny1-7-benzofuranacetic acid, 6.0 g., is heated for fifteen minutes with 3.4 g. of sulfuryl chloride in 50 ml fof benzene then left at room temperature overnight to give 2-chloro-3-phenyl-7-benzofuranacetic acid which precipitates from the reaction mixture. Recrystallization from benzene-hexane gives material of m.p. 150.5l52 C. Analysis:

7cH Calculated for C H ClO 67.l 3.9 Found: 67.3 3.8

EXAMPLE 23 Starting with 2-bromophenol and'alpha-.bromo-3,4- i

dichloroacetophenone' and using Process A as described in Examples 1 and 2, the compound :7-bromo- 3-(3,4-dichlorophenyl)-benzofuran is prepared. Using Process F as described in Examples 6 to 9, this compound is converted to 3-(3,4-dichlorophenyl)- 7-benzofuranacetic acid, m.p. l58.5-l60 C.

EXAMPLE 2 A solution of 1.0 g. of 5-methoxy-3 phenyl-7-benzofuranacetic acid in 5 ml. of acetic acid and l ml. of 47% hydriodic acid is heated at reflux for 16 hours to obtain the corresponding S-hydroxy acid. It is isolated by precipitation with water, extraction into ether and then into sodium bicarbonate solution.Recrystallization from benzene gives S-hydroxy-3-phenyl-7-benzofuranacetic acid, m.p'. l97.5l99 C. Analysis:

%C %H Calculated for C,,H ,O 7l.6 4.5 Found: 7l.1 4.6

EXAMPLE 25 Methyl 2-[7-(3-phenylbenzofuran)]propionate is obtained from methyl 2-[7-(2,3-dihydro-3-phenyllbenzofuran)]-propionate by. heating 20 g. of the latter in mediates a mixture of 5 g.

50 ml. of decalin with 5 g. of 5%.Pd/C for 24 hours. The ester can be purified by distillation or hydrolyzed as illustrated above to .2-[7-(3-phenylbenzofuran)]propionic acid.

i EXAMPLE 26 As an illustration of an acid hydrolysis of nitrile interof 3-phenyl-7-benzofuranacetonitrile in 30 ml. of acetic acid, 20 ml. of water and 20 m1. of sulfuric acid is stirred and heated at reflux overnight. On cooling and diluting with water one obtains 3-phenyl-7-benzofuranacetic acid, purified by crystallization from benzenehexane.

EXAMPLE 27 Process J, steps (1), (2) and (3) 2-[7-(3-Phenylbenzofuran)]propionic acid is also obtained by an a-methylation. A solution of 2.3 g. of 3-phenyl-7-benzofuran acetonitrile in 15 ml. of glyme is treated with 1.0 equivalents of sodium hydride and the mixture warmed until hydrogen evolution is complete. An excess, 4.0 g., of methyl iodide is added to the cooled mixture and stirred at room temperature overnight. The mixture is concentrated, mixed with 25 ml. of ethanol and 5 g. of KOH and heated at reflux overnight. Work up in the usual manner gives the desired acid.

EXAMPLE 28 2-[7-(3-phenylbenzofuran)lacrylic acid can also be reduced with sodium borohydride to the corresponding propionic acid. Five grams of the acrylic acid methyl ester is stirred at room temperature into 60 ml. of ethanol with 0.68 g. of sodium borohydride for 6' hours. The mix is diluted with water and diluted hydrochloric acid and extracted with ether. The ester is hydrolyzed in ethanol-aqueous sodium hydroxide to obtain 2-[7-(3- phenylbenzofuran)]propionic acid. 7

EXAMPLE 29 EXAMPLE 30 The following amides of the invention are prepared from the acid chloride of Example 20 by reaction with an amine as in Example 20.

o I cu ncl 011 31130 0 m ical-cs o o b o o o -continued 9 3 C CH CRH(CH H cu cucu cu wherein:

Z is hydroxyl, lower alkoxy, --Nl i -NHY, NY-Y 0 cH,),,,N

4. A method according to claim 3 wherein the compound is 3-(4-fluorophenyl)-7-benzofuranacetic acid. 5. A method according to claim 3 wherein the compound is 2 -[7-(3-phenylbenzofuran)]propionic acid.

6. A method according to claim 1 wherein R and R are hydrogen.

7. A method according to claim 6 wherein p is zero. 8. A method according to claim 1 wherein p is zero. 9. A method according to claim 8 wherein the carbon atom carrying R and R is bonded to the 6 or 7 position of the benzofuran structure.

10. A method according to claim 8 wherein n is zero. 11. A method according to claim 1 wherein the car- R is hydrogen or alkyl containing not more than two carbon atoms; R is hydrogen or, with R, forms =CH R and R are hydrogen or,'together, a carbon-carbon bond; R is hydrogen or lower alkyl, provided that when R and R form a bond, R may be halogen;

Y and Y are lower alkyl or, together, form a cyclic group selected from (CH (CH and Y is lower alkyl, lower alkoxy, halogen, nitro, diloweralkylamino or hydroxyl; Y is lower alkyl, halogen, lower haloalkyl, lower alkoxy, lower haloalkoxy, nitro, diloweralkylamino, lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl or hydroxyl;

m is 2-3; n is 0-2; p is 0-2 and r is 0-5; or a pharmaceutically acceptable salt thereof.

2. A method according to claim 1 wherein R is hydrogen.

3. A method according to claim 1 wherein R and R form a bond.

bon atom carrying R and R is bonded to the 6 or 7 position of the benzofuran structure.

12. A method according to claim 1 wherein n is zero. 13. A method according to claim 1 wherein Z is OH. 14. A method according to claim 1 wherein n is l2. 15. A method according to claim 1 wherein Z is lower alkoxy.

40 16. A method according to claim 1 wherein Z is OCH CHCH OH.

17. A method for combatting inflammatory processes in a mammalian animal which comprises administering to said animal an effective dose less than the toxic amount of a compound of the formula Page 1 of 5 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,920,828 3 DATED November 18, 1975 |NV ENTOR(S) Robert A. Scherrer It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: 0 R 0 R II I Column 3, line 7: Z-C(CH C|3" should read -Z C(CH (|3- 0 CH R 0 CH u: 1 Column 3, line 7: "HOC-CH-" should read --HOCCH- Column L, line 43: delete one vof the commas after the "'Q,"

Column 1 line 38: The first "(2)" should read -(l)--- Column 15, lines 39, +1, #3, and L5: The in each com ound name should be before the word "acrylic" and after the Column 16, lines 1, 3, 5, and 7: The in each compound name should be before the word "propionic" and after the "1" Column 19, line 3: The in the compound name should be between the word "propionic" and the "1" Column 19, line 5?: Delete the second "phenylbenzofuran" Column 20, line 20: "10 c." should be --1oo c.--

Column 20, line &2: "dimethylformaide" should read --dimethylformamide-- Column 20, line 4 1-! Delete "benzofuranacethydraxide,"

Column 20, line 45: Delete '159" and center "EXAMPLE 18" Page 2 of 5 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,920,828 DATED November 18, 1975 |NVENTOR(S) Robert A. Scherrer It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 21, line 18: The after "oil" should be Column 21, line 61: Delete one 1" in phenyllben-" Column 23, line 10:

Insert the following examples 3l- LO which were omitted:

- Example 31 2-Methyltnitrophenol is converted to 7-methyl-5- nitro-3-phenylbenzofuran by the method of Process A (Examples 1 and 2) This intermediate is brominated with N-bromosuccinimide, providing 2-bromo7-bromomethyl5-nitro-3-phenylbenzofuran which is converted by Process F,v steps land 5 to 2-bromo-5nitro-3-phenyl7benzofuranacetic acid.

Example 32 Using Processes A and F and starting with 2-bromot- (N,Ndimethylaminophenyl and phenacyl bromide one obtains 5- (N,N-dimethylamino) -3-phenyl7benzofuranacetic acid.

Example 33 3-(h-methoxyphenyl) -7-benzofuranacetic acid is acetic Page 3 of 5 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,920,828 DATED 1 November 18, 1975 lN\/ ENTOR(S) Robert A. Scherrer It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: acid is heated at reflux with t7% hydroiodic acid overnight to provide 3( t-hydroxyphenyl)7-benzofuranacetic acid.

I Example 34 Using the methods of Examples 1 and 2 and 6 to 9 and starting with -bromot-trifluoromethoxyacetophenone one obtains 3-( t-trifluoromethoxyphenyl)7benzofuranacetic acid.

Example 35 Using Process M as illustrated in Examples l t to 16,

7-methy1-3-(H-nitrophenylbenzofuran (prepared according to Process A) is converted to 2-bromo-3-( hnitrophenyl)-7-benzofuranacetic'acid.

7 Example 36 Using Processes A and F as illustrated in Examples 1 and 2 and 6 to 9 and starting with 2-bromo-H-fluorophenol and phenacyl bromide one obtains 5-fluoro-3-phenyl-7-benzofuranacetic acid.

Page 4 of 5 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 1 3,9 0,828 DATED November 18, 1975 INVENTOR(S): Robert A. Scherrer It is certified that error appears in the ab0ve-identified patent and that said Letters Patent are hereby corrected as shown below:

Example 37 The glyceryl ester of 3-phenyl-7-benzofuranacetic acid is prepared by the method described in U.S'. Patent 3, L78,O4O,

i.e. reacting the acid with chloroacetonitrile in the presence of triethylamine, heating the nitrile with 2,2-dimethyl-l,3

dioxolane3methanol in the presence of potassium carbonate and hydrolysis of the isopropylidenedioxypropyl ester.

Example 38 The potassium salt of 3-phenyl-7benzofuranacetic acid is reacted with chloromethoxymethane in dimethylformamide to provide methoxymethyl 3-phenyl-7-benzofuranacetate.

Example 32 The potassium salt of B-phenyl-7benzofuranacetic acid is reacted with chloromethyl acetate in dimethylformamide to provide acetoxymethyl 3phenyl-7-benzofuranacetate.

Page 5 of 5 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,920,828 DATED November 18, 1975 |NVENTOR(S) Robert A. Scherrer It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Example LO By the procedures illustrated in Examples 1 and 2 and 6 to 9, and starting with flph abromoacetophenone and 2bromo- L-i; butylphenol one obtains 5- t -butyl-3-phenyl7- benzofuranaoetic acid, m.p MOE-1 8 C.

Claim 1, line 27: "-NY- Y should read -NY Y Claim 1, line Mt: CH3 should read "-(CH2)2N(CH2)2;" t

Signed and Sealed this [SEAL] Twemy'eighth of September 1976 A trest:

RUTH C. MASON Arresting Officer C. MARSHALL DANN (mnmissimu'r 0f Palenls and Trademarks 

1. A METHOD FOR COMBATTING INFLAMMATORY PROCESSES IN A MAMMALIAN ANIMAL WHICH COMPRISES ADMINISTERING TO SAID ANIMAL AN EFFECTIVE DOSE LESS THAN THE TOXIC AMOUNT OF A COMPOUND OF THE FORMULA
 2. A method according to claim 1 wherein R5 is hydrogen.
 3. A method according to claim 1 wherein R3 and R4 form a bond.
 4. A method according to claim 3 wherein the compound is 3-(4-fluorophenyl)-7-benzofuranacetic acid.
 5. A method according to claim 3 wherein the compound is 2-(7-(3-phenylbenzofuran))propionic acid.
 6. A method according to claim 1 wherein R3 and R4 are hydrogen.
 7. A method according to claim 6 wherein p is zero.
 8. A method according to claim 1 wherein p is zero.
 9. A method according to claim 8 wherein the carbon atom carrying R1 and R2 is bonded to the 6 or 7 position of the benzofuran structure.
 10. A method according to claim 8 wherein n is zero.
 11. A method according to claim 1 wherein the carbon atom carrying R1 and R2 is bonded to the 6 or 7 position of the benzofuran structure.
 12. A method according to claim 1 wherein n is zero.
 13. A method according to claim 1 wherein Z is OH.
 14. A method according to claim 1 wherein n is 1-2.
 15. A method according to claim 1 wherein Z is lower alkoxy.
 16. A method according to claim 1 wherein Z is
 17. A method for combatting inflammatory processes in a mammalian animal which comprises administering to said animal an effective dose less than the toxic amount of a compound of the formula 